scholarly journals De novo design of functional zwitterionic biomimetic material for immunomodulation

2020 ◽  
Vol 6 (22) ◽  
pp. eaba0754 ◽  
Author(s):  
Bowen Li ◽  
Zhefan Yuan ◽  
Priyesh Jain ◽  
Hsiang-Chieh Hung ◽  
Yuwei He ◽  
...  
Keyword(s):  
De Novo ◽  
Specific Interaction ◽  
De Novo Design ◽  
The Other ◽  
Trade Off ◽  
Zwitterionic Polymers ◽  
Zwitterionic Polymer ◽  
Nonspecific Interactions ◽  
Immunomodulatory Properties

Superhydrophilic zwitterionic polymers are a class of nonfouling materials capable of effectively resisting any nonspecific interactions with biological systems. We designed here a functional zwitterionic polymer that achieves a trade-off between nonspecific interactions providing the nonfouling property and a specific interaction for bioactive functionality. Built from phosphoserine, an immune-signaling molecule in nature, this zwitterionic polymer exhibits both nonfouling and immunomodulatory properties. Its conjugation to uricase is shown to proactively eradicate all unwanted immune response, outperforming the zwitterionic polymers. On the other hand, this polymer could significantly prolong the half-life of protein drugs in vivo, overcoming the innate drawback of phosphoserine in inducing accelerated clearance. Our demonstration of a nonfouling zwitterionic material with built-in immunomodulatory functionality provides new insights into the fundamental design of biomaterials, as well as far-reaching implications for broad applications such as drug delivery, implants, and cell therapy.

scholarly journals Exploitation of De Novo Helper-Lipids for Effective Gene Delivery.

2009 ◽  
Vol 11 (4) ◽  
pp. 56 ◽  
Author(s):  
Tomoaki Kurosaki ◽  
Takashi Kitahara ◽  
Mugen Teshima ◽  
Koyo Nishida ◽  
Junzo Nakamura ◽  
...  
Keyword(s):  
Gene Delivery ◽  
De Novo ◽  
Transfection Efficiency ◽  
The Other ◽  
Penetration Enhancers ◽  
Cell Toxicity ◽  
In Vivo Transfection ◽  
In Vitro Transfection

Purpose: In gene delivery, a fusogenic lipid such as dioleyl phosphatidylethanolamine (DOPE) which is a component of cationic liposomal vector is important factor for effective transfection efficiency. We investigated the effect of penetration enhancers as alternative helper-lipids to DOPE. Methods: Transdermal penetraion enhancers such as N-lauroylsarcosine (LS), (R)-(+)-limonene (LM), vitamin E (VE), and phosphatidyl choline from eggs (EggPC) were used in this experiments as helper-lipids with N-[1-(2, 3-dioleyloxy) propyl]-N, N, N-trimethlylammonium chloride (DOTMA) and cholesterol (CHOL). We examined in vitro transfection efficiency, cytotoxicity, hematotoxicity, and in vivo transfection efficiency of plasmid DNA/cationic liposomes complexes. Results: In transfection experiments in vitro, the cationic lipoplexes containing LS had highest transfection efficiency among the other lipoplexes independently of FBS. Furthermore, the lipoplexes containing LS had lowest cell toxicity among the other lipoplexes in the presence of FBS. As the results of erythrocytes interaction experiment, DOTMA/LS/CHOL, DOTMA/VE/CHOL, and DOTMA/EggPC/CHOL lipoplexes showed extremely lower hematotoxicity. On the basis of these results, the in vivo transfection efficiencies of the lipoplexes were examined. The lipoplexes containing LS had the highest transfection activity among the other lipoplexes. Conclusion: In conclusion, several transdermal penetration enhancers are available for alternative helper-lipids to DOPE in cationic liposomal vectors. Among them, DOTMA/LS/CHOL lipoplexes showed superior characteristics in in vitro transfection efficiency, cell toxicity, hematotoxicity, and in vivo transfection efficiency.

scholarly journals Self-assembly of large RNA structures: learning from DNA nanotechnology

2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Jaimie Marie Stewart ◽  
Elisa Franco
Keyword(s):  
Self Assembly ◽  
De Novo ◽  
Dna Nanotechnology ◽  
De Novo Design ◽  
Dna Nanostructures ◽  
Rna Structures ◽  
Functional Nanostructures ◽  
Rna And Dna ◽  
Unique Chemical

AbstractNucleic acid nanotechnology offers many methods to build self-assembled structures using RNA and DNA. These scaffolds are valuable in multiple applications, such as sensing, drug delivery and nanofabrication. Although RNA and DNA are similar molecules, they also have unique chemical and structural properties. RNA is generally less stable than DNA, but it folds into a variety of tertiary motifs that can be used to produce complex and functional nanostructures. Another advantage of using RNA over DNA is its ability to be encoded into genes and to be expressed in vivo. Here we review existing approaches for the self-assembly of RNA and DNA nanostructures and specifically methods to assemble large RNA structures. We describe de novo design approaches used in DNA nanotechnology that can be ported to RNA. Lastly, we discuss some of the challenges yet to be solved to build micron-scale, multi stranded RNA scaffolds.

scholarly journals Designed for life: biocompatible de novo designed proteins and components

2018 ◽  
Vol 15 (145) ◽  
pp. 20180472 ◽  
Author(s):  
Katie J. Grayson ◽  
J. L. Ross Anderson
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Building Blocks ◽  
De Novo Design ◽  
Biochemical Processes ◽  
Designed Proteins ◽  
De Novo Protein Design ◽  
Protein Molecules ◽  
And Function

A principal goal of synthetic biology is the de novo design or redesign of biomolecular components. In addition to revealing fundamentally important information regarding natural biomolecular engineering and biochemistry, functional building blocks will ultimately be provided for applications including the manufacture of valuable products and therapeutics. To fully realize this ambitious goal, the designed components must be biocompatible, working in concert with natural biochemical processes and pathways, while not adversely affecting cellular function. For example, de novo protein design has provided us with a wide repertoire of structures and functions, including those that can be assembled and function in vivo . Here we discuss such biocompatible designs, as well as others that have the potential to become biocompatible, including non-protein molecules, and routes to achieving full biological integration.

scholarly journals De Novo Design of Polymeric Carrier to Photothermally Release Singlet Oxygen for Hypoxic Tumor Treatment

Research ◽  
2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Tianci Huang ◽  
Menglong Zhao ◽  
Qi Yu ◽  
Zheng Feng ◽  
Mingjuan Xie ◽  
...  
Keyword(s):  
Singlet Oxygen ◽  
De Novo ◽  
Inhibitory Effect ◽  
De Novo Design ◽  
Tumor Treatment ◽  
Polymer Carrier ◽  
Hypoxic Environment ◽  
Therapeutic Platform

Intratumoral hypoxia extremely limits the clinic applications of photodynamic therapy (PDT). Endoperoxides allow thermally releasing singlet oxygen (1O2) in a defined quantity and offer promising opportunities for oxygen-independent PDT treatment of hypoxic tumors. However, previous composite systems by combining endoperoxides with photothermal reagents may result in unpredicted side effects and potential harmful impacts during therapy in vivo. Herein, we de novo design an all-in-one polymer carrier, which can photothermally release 1O2. The strategy has been demonstrated to effectively enhance the production of 1O2 and realize the photodamage in vitro, especially in hypoxic environment. Additionally, the polymer carrier accumulates into tumor after intravenous injection via the enhanced permeation and retention effects and accelerates the oxygen-independent generation of 1O2 in tumors. The oxidative damage results in good inhibitory effect on tumor growth. Realization of the strategy in vivo paves a new way to construct photothermal-triggered oxygen-independent therapeutic platform for clinical applications.

scholarly journals Cryptococcus gattii VGI Subtypes: Geographical Distribution, Molecular Traits, and Virulence Difference

2021 ◽  
Author(s):  
Xinying Xue ◽  
Wei Tang ◽  
Xuelei Zang ◽  
Weixin Ke ◽  
Yuxia Liu ◽  
...  
Keyword(s):  
Geographical Distribution ◽  
Species Complex ◽  
Reference Genome ◽  
De Novo ◽  
Cryptococcus Gattii ◽  
The Other ◽  
Molecular Type ◽  
Life Threatening

Abstract Background: As a life-threatening fungus, Cryptococcus gattii (C gattii) species complex is emerging worldwide. However, the geographical distribution, molecular traits, and virulence difference are poorly characterized in China.Results: From 2011 to 2017, we collected 32 strains of C gattii from 18 hospitals across China, of which 27 [84·4%] strains molecular traits were profiled by whole-genome sequencing (WGS) and multi-locus sequence typing (MLST) and compared with strains previously described in China from 2006 to 2020. Totally 119 clinical cases caused by C gattii strains (87 in previous reports and 32 in our study) distributed widely in 20 provincial-level administrative regions of China, of which 114 strains molecular types were obtained. The majority molecular type was VGI (81/114, 71·1%) and the other was VGII (33/114, 28·9%). Four major subtypes of VGI (VGIa, VGIb, VGIc, and VGId) were revealed from global C gattii VGI (n=308), respectively accounting for 52·9% (163/308), 36·0% (111/308), 3·9% (12/308), and 4·2% (13/308). The other nine strains could not be assigned to these four subtypes clearly. Our clinical data suggested that VGIb cases had a worse clinical outcome than VGIa, which was consistent with in vitro and in vivo experiments. In addition, a candidate virulence SNP on SOD2 in VGIa was initially identified by comparing high-quality de novo reference genome.Conclusions: The geographical distribution of C gattii species complex was first described in China. C gattii VGI could be clearly segregated into four major subtypes based on genomics profiles and VGIb was more virulent than VGIa in China. Our study suggests the molecular type of C gattii is necessary for personalized treatment in clinic.

scholarly journals CReM: chemically reasonable mutations framework for structure generation

2020 ◽  
Author(s):  
Pavel Polishchuk
Keyword(s):  
Deep Learning ◽  
De Novo ◽  
Chemical Space ◽  
De Novo Design ◽  
The Other ◽  
Learning Models ◽  
Structure Generation ◽  
Design Studies ◽  
Flexible Control ◽  
New Framework

Abstract Structure generators are widely used in de novo design studies and their performance substantially influences an outcome. Approaches based on the deep learning models and conventional atom-based approaches may result in invalid structures and fail to address their synthetic feasibility issues. On the other hand, conventional reaction-based approaches result in synthetically feasible compounds but novelty and diversity of generated compounds may be limited. Fragment-based approaches can provide both better novelty and diversity of generated compounds but the issue of synthetic complexity of generated structure was not explicitly addressed before. Here we developed a new framework of fragment-based structure generation that, by design, results in the chemically valid structures and provides flexible control over diversity, novelty, synthetic complexity and chemotypes of generated compounds. The framework was implemented as an open-source Python module and can be used to create custom workflows for the exploration of chemical space.

scholarly journals De novo design of symmetric ferredoxins that shuttle electrons in vivo

2019 ◽  
Vol 116 (29) ◽  
pp. 14557-14562 ◽  
Author(s):  
Andrew C. Mutter ◽  
Alexei M. Tyryshkin ◽  
Ian J. Campbell ◽  
Saroj Poudel ◽  
George N. Bennett ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Electron Transfer ◽  
Gene Duplication ◽  
Sequence Space ◽  
Metabolic Pathway ◽  
De Novo ◽  
Phylogenetic Analyses ◽  
De Novo Design ◽  
Symmetric Molecule

A symmetric origin for bacterial ferredoxins was first proposed over 50 y ago, yet, to date, no functional symmetric molecule has been constructed. It is hypothesized that extant proteins have drifted from their symmetric roots via gene duplication followed by mutations. Phylogenetic analyses of extant ferredoxins support the independent evolution of N- and C-terminal sequences, thereby allowing consensus-based design of symmetric 4Fe-4S molecules. All designs bind two [4Fe-4S] clusters and exhibit strongly reducing midpoint potentials ranging from −405 to −515 mV. One of these constructs efficiently shuttles electrons through a designed metabolic pathway inEscherichia coli. These finding establish that ferredoxins consisting of a symmetric core can be used as a platform to design novel electron transfer carriers for in vivo applications. Outer-shell asymmetry increases sequence space without compromising electron transfer functionality.

scholarly journals Modification of Three Amino Acids in Sodium Taurocholate Cotransporting Polypeptide Renders Mice Susceptible to Infection with Hepatitis D VirusIn Vivo

2016 ◽  
Vol 90 (19) ◽  
pp. 8866-8874 ◽  
Author(s):  
Wenhui He ◽  
Zhiliang Cao ◽  
Fengfeng Mao ◽  
Bijie Ren ◽  
Yunfei Li ◽  
...  
Keyword(s):  
Amino Acids ◽  
Monoclonal Antibody ◽  
De Novo ◽  
Genetic Manipulation ◽  
Specific Interaction ◽  
Sodium Taurocholate ◽  
Hepatitis D ◽  
Hdv Infection ◽  
Functional Receptor

ABSTRACTSodium taurocholate cotransporting polypeptide (NTCP) was identified as a functional receptor for hepatitis D virus (HDV) and its helper hepatitis B virus (HBV). In cultured cell lines, HDV infection through mouse NTCP is restricted by residues 84 to 87 of the receptor. This study shows that mice with these three amino acids altered their corresponding human residues (H84R, T86K, and S87N) in endogenous mouse NTCP supportde novoHDV infectionin vivo. HDV infection was documented by the presence of replicative forms of HDV RNA and HDV proteins in liver cells at day 6 after viral inoculation. Monoclonal antibody specifically binding to the motif centered on K86 in NTCP partially inhibited HDV infection. These studies demonstrated specific interaction between the receptor and the viral envelopesin vivoand established a novel mouse model with minimal genetic manipulation for studying HDV infection. The model will also be useful for evaluating entry inhibitors against HDV and its helper HBV.IMPORTANCENTCP was identified as a functional receptor for both HDV and HBV in cell cultures. We recently showed that neonatal C57BL/6 transgenic (Tg) mice exogenously expressing human NTCP (hNTCP-Tg) in liver support transient HDV infection. In this study, we introduced alterations of three amino acids in the endogenous NTCP of FVB mice through genome editing. The mice with the humanized NTCP residues (H84R, T86K, and S87N) are susceptible to HDV infection, and the infection can be established in both neonatal and adult mice with this editing. We also developed a monoclonal antibody specifically targeting the region of NTCP centered on lysine residue 86, and it can differentiate the modified mouse NTCP from that of the wild type and partially inhibited HDV infection. These studies shed new light on NTCP-mediated HDV infectionin vivo, and the NTCP-modified mice provide a useful animal model for studying HDV infection and evaluating antivirals against the infection.

scholarly journals B CELL ACTIVATION IN VIVO BY NONANTIGEN-SPECIFIC INTERACTION WITH T CELLS

1972 ◽  
Vol 136 (2) ◽  
pp. 381-386 ◽  
Author(s):  
T. Tito ◽  
G. M. Shearer ◽  
D. Trizio ◽  
G. Cudkowicz
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cell Activation ◽  
Bone Marrow Cells ◽  
Specific Interaction ◽  
The Other ◽  
B Cell Activation ◽  
Bone Marrow Precursor ◽  
Thymus Cells

The number of direct (γM) hemolytic plaque responses of irradiated mice, repopulated with relatively small and limiting numbers of bone marrow and thymus cells, was increased by the simultaneous immunization with two antigen complexes instead of one. Anti-sheep responses were augmented by the following antigen combinations: SRBC + HRBC, SRBC + BRBC, and SRBC + CRBC. Limiting either thymocytes or bone marrow cells indicated that the antigen mixtures acted at the level of T cells increasing severalfold the number of triggered antigen-reactive cells. It was concluded that one of the antigens could have influenced the triggering of antigen-reactive cells specific for the other by promoting synergistic or derepressive T-T cell interactions. Moreover, bone marrow precursor cells could have been activated by the thymic inducers specific for the test antigens as well as by those specific for the second of the priming antigens.

De Novo Design of Chemical Stability Near-Infrared Molecular Probes for High-Fidelity Hepatotoxicity Evaluation In Vivo

2019 ◽  
Vol 141 (15) ◽  
pp. 6352-6361 ◽  
Author(s):  
Dan Cheng ◽  
Juanjuan Peng ◽  
Yun Lv ◽  
Dongdong Su ◽  
Dongjie Liu ◽  
...  
Keyword(s):  
Chemical Stability ◽  
Near Infrared ◽  
De Novo ◽  
De Novo Design ◽  
Molecular Probes ◽  
High Fidelity
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